s12916 014 0178 2

Goldschneider et al.
BMC Medicine 2014, 12:178

http://www.biomedcentral.com/1741-7015/12/178
GUIDELINE
Open Access
Pain care for patients with epidermolysis bullosa:

best care practice guidelines
Kenneth R Goldschneider1*, Julie Good2, Emily Harrop3, Christina Liossi4,5, Anne Lynch-Jordan6, Anna E Martinez7,
Lynne G Maxwell8 and Danette Stanko-Lopp9
Abstract
Background: Inherited epidermolysis bullosa (EB) comprises a group of rare disorders that have multi-system effects
and patients present with a number of both acute and chronic pain care needs. Effects on quality of life are substantial.
Pain and itching are burdensome daily problems. Experience with, and knowledge of, the best pain and itch care for
these patients is minimal. Evidence-based best care practice guidelines are needed to establish a base of knowledge and
practice for practitioners of many disciplines to improve the quality of life for both adult and pediatric patients with EB.
Methods: The process was begun at the request of Dystrophic Epidermolysis Bullosa Research Association International
(DEBRA International), an organization dedicated to improvement of care, research and dissemination of knowledge for
EB patients worldwide. An international panel of experts in pain and palliative care who have extensive experience
caring for patients with EB was assembled. Literature was reviewed and systematically evaluated. For areas of care
without direct evidence, clinically relevant literature was assessed, and rounds of consensus building were conducted.
The process involved a face-to-face consensus meeting that involved a family representative and methodologist, as well
as the panel of clinical experts. During development, EB family input was obtained and the document was reviewed by
a wide variety of experts representing several disciplines related to the care of patients with EB.
Results: The first evidence-based care guidelines for the care of pain in EB were produced. The guidelines are clinically
relevant for care of patients of all subtypes and ages, and apply to practitioners of all disciplines involved in the care of
patients with EB. When the evidence suggests that the diagnosis or treatment of painful conditions differs between
adults and children, it will be so noted.
Conclusions: Evidence-based care guidelines are a means of standardizing optimal care for EB patients, whose disease is
often times horrific in its effects on quality of life, and whose care is resource-intensive and difficult. The guideline
development process also highlighted areas for research in order to improve further the evidence base for future care.
Keywords: Epidermolysis bullosa, Pain, Practice guidelines, RDEB, DEBRA, Acute pain, Chronic pain, Recessive dystrophic
epidermolysis bullosa, Dystrophic Epidermolysis Bullosa Research Association International
Background
Inherited epidermolysis bullosa (EB) comprises a group of
rare disorders, generally thought of as skin diseases. However, EB has multi-system effects and patients present with
a number of both acute and chronic pain care needs [1].
Effects on quality of life are substantial [2,3]. Due to its
low prevalence, expertise in pain care for patients with this
disease is often restricted to a few specialized care centers.
* Correspondence: Kenneth.goldschneider@cchmc.org
1
Pain Management Center, Department of Anesthesiology, Cincinnati Childrens
Hospital Medical Center, Cincinnati, Ohio, USA
Full list of author information is available at the end of the article
Even then, evidence-based pain care is limited by a near

absence of scientific literature specific to EB. This set of
guidelines was requested by Dystrophic Epidermolysis
Bullosa Research Association International (DEBRA International) to help standardize the approach to pain care for
both adult and pediatric patients with EB in all parts of
the world. Consequently, a group of clinical pain care experts from a few countries have come together to lend
their experience to the limited scientific literature to create these guidelines.
The present guidelines on pain care for patients with
EB are based on a review and synthesis of the available
2014 Goldschneider et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public
Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this
article, unless otherwise stated.
Goldschneider et al. BMC Medicine 2014, 12:178

literature, guided by expert consensus and thoughtful

application of theory. The guidelines are divided into
four topics: psychological treatment of pain and pruritus,
acute pain, chronic and recurrent pain, and special
topics. The Psychological and Integrative Treatments
section leads off because the information it contains
applies to all the topics that follow. The Acute Pain
section focuses on postoperative pain. The Chronic
and Recurrent Pain section includes dressing changes,
baths, skin pain and joint and other body pains. The
Special Topics section includes pain care in infants
with EB and pain care at the end of life. While not pain
per se, itching is a major source of discomfort [4] and
is also discussed.
The aim of the guidelines is to provide the user with
information on pain care for children and adults with
EB. These guidelines can be applied to all patients diagnosed with hereditary forms of EB. Patients with acquired forms are not included in the guidelines. The
guidelines contain two types of guidance. Recommendations are graded and highlighted in text boxes at the end
of the manuscript. Good Practice Points are located at
the end of each topical section and summarize concepts
and best practices, based on the clinical experience of
the guidelines development group.
The daily routine of many patients with severe forms
of EB will have a number of painful events, each of
which may suggest the need for intervention. However,
addressing each one pharmacologically may lead to a
level of sedation that prevents a meaningful level of
productivity. It is important to discuss the needs of the
patient and the options for caring for those needs with
the patient and family. Together, the patient, family and
practitioner can transform the guidelines into an individualized care plan. It is to be expected that each patients
needs will be dynamic; periodic review of the needs and
goals will optimize care at each step of the patients life.
Of note, the term EB will be used throughout the
text. However, four major types of EB are known and
are categorized as Simplex (EBS), Junctional (JEB), dystrophic types (DEB) and Kindler Syndrome. A recent
consensus statement was released that reclassified the
subtypes further based on anatomic location within the
skin and pattern of involvement, and discouraged the use
of eponyms (with the exception of Kindler Syndrome).
EBS is sub-typed as EBS suprabasal and EBS basal, JEB
as JEB generalized and JEB localized, DEB as Recessive
DEB and Dominant DEB (RDEB and DDEB, respectively) [5]. Additionally, there are at least 18 genes associated with the different types of EB [5]. The proposed
new classification does not address the relation to painful conditions, and, thus, the four major types will be
referenced throughout the guidelines. There is a wide
range of severity within the types. EBS is usually due to
Page 2 of 23
autosomal dominant mutations in keratin 5 or 14 or in

plectin and is often of milder severity. JEB can result
from mutations in any of six different basement membrane components, is inherited as an autosomal recessive disorder, and can range from mild to fatal early in
life. DEB can be in a mild dominant form (DDEB) or a
more severe recessive one (RDEB), both due to mutations in collagen 7. The recommendations that follow
are intended to be generally applicable to all patients
with EB who experience pain. The pain conditions vary
in prevalence among the types of EB, and readers will
find relevant guidelines to apply in the care of the particular pain problems they and their patients face. Resources (for example, particular medications and formulations,
trained medical, nursing and therapy personnel) will
vary by location, and practitioners and families will,
therefore, need to adapt the recommendations based
on what is available in their locale. DEBRA International
[6] is an optimal facilitating organization that can aid
implementation of the guidelines by way of providing
information, support and means of contacting expert
care providers.
Methods
In 2011, a multidisciplinary working group formed to
develop best care practice guidelines for pain associated
with EB. The group comprised representatives from
nursing, medicine and psychology who were expert in
the clinical care of patients with EB. Guidelines topics
and subtopics were chosen by the multidisciplinary
group with input from outside clinicians, based on issues
presented in the literature, seen clinically and raised for
discussion at DEBRA International Congress meetings.
Individuals or small groups were assigned to the various
subtopics. After relevant literature was reviewed, preliminary recommendations for each subsection were made.
Recommendations were circulated by email among the
entire panel of experts for review and input/feedback
was incorporated. Initial citations were added or removed as required for accuracy and appropriateness,
and criticism made of areas of weakness. Thus, the
group formed the first iteration of expert consensus. The
revised recommendations were recirculated to the group
for review, to establish consensus more firmly. A panel
of outside reviewers, comprising both clinicians and patients/families, then reviewed the document for comprehensibility, omissions and applicability.
Following external review (see Acknowledgements for
reviewers), funding became available and a subsequent
systematic evidence review was conducted by a trained
methodologist (author DSL). Clinical questions and the
systematic search strategy were developed, based on the
guideline topics and subtopics from the working group.
The population of interest comprises patients with pain

who have any variant of EB. The interventions included,

but were not limited to, pharmacological, holistic, psychological, psychical therapy and/or environmental interventions. Outcomes of interest were improvement in
symptom control (for example, pain, itch) and level of
function.
Systematic literature searches were conducted using
MedLine, CINAHL, PsycInfo and The Cochrane Library.
Search terms for epidermolysis bullosa and pain, regional anesthesia, or nerve block were used as medical
subject headings and/or keywords in all databases. The
search was only limited to articles published in English.
No other restrictions, limits or filters were used. Publication dates were not restricted for any topic or subtopic,
as the diagnosis is rare and there were few studies of
higher level, directly-related evidence (that is, systematic
reviews, meta-analyses, randomized controlled trials).
Reference lists were searched to identify studies. Studies
submitted by the working group and used in the initial
consensus processes were also reviewed. The most recent systematic search for pediatric acute, chronic, or recurrent pain management in EB patients was conducted
in December 2011.
Citations from the evidence searches were reviewed by
title and abstract for potential inclusion, regardless of
study design (n = 1,061). Evidence related to the clinical
questions from systematic reviews, meta-analyses and
RCTs as well as observational studies, case reports and
expert opinion articles were reviewed (see Figure 1). A
total of 57 references were found and evaluated that
were specific to the cross match of EB and the painrelated keywords (see above), of which only 8 were included into specific recommendations. The rationale for
including and excluding these references is found in
Table 1 and in Additional file 1.
Page 3 of 23
All included articles were critically appraised using evidence appraisal forms from the LEGEND (Let Evidence
Guide Every New Decision) evidence evaluation system
[7,8]. The methodologist assessed risk of bias in the included studies by evaluating quality for all individual
studies by domain and study design. The quality levels
for included studies were recorded (see Table 2). The
reader will find the evidence level for each article used
to directly support each recommendation noted after its
citation in the Reference section of the Summary of recommendations (Table 3). Age specificity of each recommendation is also noted. Data were collected on
descriptive characteristics of patients, characteristics of
the pain management interventions, and associated outcomes of reported pain management interventions.
Using the Grade for the Body of Evidence tool in the LEGEND system [7] provided objective criteria for evaluating evidence related to each recommendation (see
Table 4).
Given the paucity of data for statistical analysis, it was
deemed appropriate to conduct a face-to-face consensus
meeting on 4, 5 May 2012 in Cincinnati, OH. The LEGEND tool for Judging the Strength of a Recommendation (see Table 4) was used as a guide for finalizing
recommendation statements by discussing the body of
evidence and discussing safety/harm and other dimensions [7]. The overall GRADE (A, B, C, D) for each recommendation statement was then determined, based on
this process and the established criteria for GRADE
[9,10].
Updating procedure
The guidelines will be updated every three years after

the first version. If new relevant evidence is detected before the update, the information will be published on the
1,046 records identified through

database searches
1,160 records identified
114 records identified from the
working group
120 duplicates removed
1,040 records screened by title
and abstract review
787 records excluded
253 records reviewed
in full text for eligibility
196 records included in

guideline body of evidence
57 records excluded
(not related to the clinical question,
once reviewed in full text)
Figure 1 Flow of information through the evidence evaluation process.

Page 4 of 23
Table 1 EB-specific articles used in producing recommendations

Study citation
Study type
Population (setting, patients)
Intervention/Comparison groups
Outcomes
Chiu 1999 [68]
Case report
Country: Canada Setting: Childrens

Hospital Age: 11 years Gender:
Male Patient with Severe JEB
Amitryptiline (25 mg at night) was

prescribed and patient started on a
program of cognitive behavioral
training (hypnotic imagery, distraction).
Oral midazolam (7.5 mg) was initiated
20 minutes prior to bath or dressing
change
Pain management
Goldschneider
2010 [41,42]
Review articles
Country: United States Setting:

Childrens Hospital Patients
with EB
Pain management and prevention
Pain management
Herod 2002 [44]
Review article
Country: England (London) Setting:

Childrens Hospital Patients with EB
General pain management
Pain management
Mellerio 2007 [152]
Review article
Country: United States, England,

Chile Setting: Hospital Patients
with EB
Medical management
General pain management
Saroyan 2009 [156]
Case report

Hospital Female infant with EBS,
severe, Dowling-Meara subtype
Use of IV ketamine given orally Oral

administration of IV ketamine (10 mgmL,
Monarch Pharmaceuticals) at a starting
dose of 0.5 mg (0.125 mgkg dose) Over
four days, the dose was titrated to 3 mg
(0.75 mgkgdose) in response to observed
effect
Achieve analgesia during

painful dressing changes
van Scheppingen
2008 [4]
Qualitative study
(Interviews)
Country: Netherlands Setting:

Center for Blistering Diseases
Age: 6 to 18 years Children
with different (sub)types of EB)
Interviews conducted at homes or in hospital

Questions explored were: (i) What problems
do children with EB actually experience as
being the most difficult? (ii) What is the
impact of these problems on their daily life?
(iii) Are there differences in experiences
between mildly and severely affected
children?
Themes of pain for severe

disease (generalized blistering
with motion impairment) and
for mild disease (localized
blistering or generalized
blistering without motion
impairment).
Watterson 2004 [74]
Case report

Hospital Children with EB using
peripheral opioids
Topical morphine gel applied to the most

painful areas of skin at that time for each
child
Pain scores
EB, epidermolysis bullosa, EBS, epidermolysis bullosa simples; JEB, junctional epidermolysis bullosa.
web page for DEBRA International that is dedicated to

clinical the Pain guidelines [11].
Results and discussion

Psychological and integrative approaches
Introduction
A biopsychosocial approach emphasizing medical, psychological and physical therapies for pain management
has been suggested to be the most useful for adults and
Table 2 Evidence levels [8]
Quality level
Definition
1aa or 1ba
Systematic review, meta-analysis,

or meta-synthesis of multiple studies
2a or 2b
Best study design for domain
3a or 3b
Fair study design for domain
4a or 4b
Weak study design for domain
5a or 5b
General review, expert opinion,

case report, consensus report,
or guideline
Local Consensus
a = good quality study; b = lesser quality study.
children with acute and chronic pain [12]. This approach

has also been advocated for EB patients [3] and should
be initiated from early in youth and modified with maturation. It is recommended that psychological interventions be used in conjunction with physical and
pharmacologic therapies.
Types of therapies
Psychological therapies for pain management have been

shown to modify pain intensity, reduce related distress,
decrease pain-related functional disability and improve
pain coping. Painful experiences amenable to treatment
include acute pain related to procedures (for example,
whirlpool treatments) or medical routines (for example,
bandage changes, bathing), and chronic pain conditions
such as headache, abdominal pain or other disease-related
conditions. Psychological therapies include cognitive behavioral therapy (CBT), hypnosis, biofeedback and relaxation training, among others. CBT focuses on changing
the catastrophic thinking and negative emotions surrounding pain as well as modifying lifestyle to promote
wellness behavior despite chronic pain [13]. Hypnosis is a

Page 5 of 23
Table 3 Summary of recommendations

Application
Level of
Target age Key references (evidence grade)
recommendation group
A. Psychological therapies offer effective approaches to management of chronic and acute pain as well as itching.
For chronic pain management use cognitive behavioral
therapy (CBT).
All
Gerik 2005 [13] (5a), Palermo 2005 [17] (5a)
For acute pain management, offer the patient distraction,

hypnosis, visualization, relaxation or other forms of CBT
All
Green 2005 [14] (5a), Uman 2006 [21]
Consider habit reversal training, and other psychological

techniques for management of pruritus
All
Chida 2007 [29] (1a), Ehlers 1995 [32] (2b), Azrin 1973 [30]
(4b), Hagermark 1995 [28] (5a), Rosenbaum 1981 [31] (5a)
B. Postoperative pain can be handled as for other patients in the same setting, with modifications.
Basic perioperative assessment and pain treatments
should be used as for non-EB patients, with modification
All
Goldschneider 2010 [41] (5a), Goldschneider 2010b [42] (5a)
Transmucosal (including intranasal fentanyl and

transbuccal opioids) should be considered for short
procedures and pain of brief duration when intravenous
and enteral routes are unavailable
All
Manjushree et al., 2002 [45] (2b); Borland et al., 2007 [46]

(2b); Desjardins et al., 2000 [47] (2a)
Perioperative opioid use must account for preoperative

exposure, with appropriate dose increases to account for
tolerance
All
Hartrick 2008 [56] (1a), Mhuircheartaigh 2009 [55] (1a),

Viscusi 2005 [54] (2a)
Regional anesthesia is appropriate for pain resulting from

a number of major surgeries. Dressing of catheters must
be non-adhesive and monitored carefully
All
Diwan 2001 [51] (5a), Doi 2006 [53] (5b), Englbrecht

2010 [52] (5a), Kelly 1988 [48] (5b), Sopchak 1993 [49] (5a),
Yee 1989 [50] (5a)
C. Skin wounds and related pain are the hallmark of EB of most subtypes. Prevention and rapid healing of wounds through activity
pacing, optimal nutrition and infection control are important. A number of pharmacologic treatments are available
Maintain optimal nutrition and mobility and treat
infections as indicated
All
Denyer 2010 [57] (5a)
Consider topical therapies for pain
All
Cepeda 2010 [77] (1a), Lander 2006 [76] (1a), LeBon 2009
[73] (1a), Twillman 1999 [72] (5a), Watterson 2004 [74](5a)
Systemic pharmacologic therapy should be adapted to

treat both acute and chronic forms of skin pain
All
Noble 2010 [59] (1a), Moore, 2011 [ 67] (1a), Nicholson

2009 [65] (1a)
Monitor potential long-term complications of chronically

administered medications
Pediatric
Huh 2010 [62] (4a), Camilleri 2011 [66] (5a), Chiu 1999 [68]
(5a), Cruciani 2008 [63] (5a), Gray 2008 [69] (5a)
D. Baths and dressing changes require attention to both pain and anxiety
Anxiolytics and analgesics should be used for procedural
pain and fear. Care must be taken when combining such
medications due to cumulative sedative effects
All
Bell 2009 [85] (1a), Blonk 2010 [84] (1b), Ezike 2011 [82]
(2a), Desjardins 2000 [47] (2a), Borland 2007 [46] (2b),
Manjushree 2002 [45] (2b), Humphries 1997 [83] (2b),
Wolfe 2010 [81] (5a), Ugur 2009 [86] (5a)
Cognitive behavioral techniques should be implemented

as the child becomes old enough to use them
effectively. Specifically, distraction should be used for
younger children
All
Green 2005 [14] (5a); Gerik 2005 [13] (5a), Palermo 2005
[17] (5a)
Environmental measures such as adding salt to the water

to make it isotonic and keeping the room warm are
recommended
All
Arbuckle 2010 [78] (5a), Cerio 2010 [79] (5a), Peterson

(Poster) 2011 [80] (5b)
E. EB affects the gastrointestinal tract in its entirety. Pain from ulcerative lesions responds to topical therapy. GERD and esophageal
strictures have nutritional as well as comfort implications and should be addressed promptly when found. Maintaining good bowel habits
and reducing iatrogenic causes of constipation are crucial.
Topical treatments are recommended for oral and
perianal pain
All
Ergun 1992 [98] (4a), Travis 1992 [97] (4b), Marini 2001
[99] (5a), Buchsel 2008 [100] (5a), Buchsel 2003 [101] (5b),
Cingi 2010 [102] (2a)
Therapy should be directed to manage gastroesophageal

reflux and esophageal strictures using standard
treatments
All
Freeman 2008 [95] (4a)
Constipation should be addressed nutritionally, with

hydration and addition of fiber in the diet to keep stool
soft, by minimizing medication-induced dysmotility and
with stool softeners
All
Belsey 2010 [112] (1a), Freeman 2008 [98] (4a), Hanson

2006 [113] (4a)

Page 6 of 23
Table 3 Summary of recommendations (Continued)

F. Bone pain treatment must account for factors that include nutrition, mobility, potential occult fractures and is treated by combinations of
nutritional, physical, pharmacologic and psychological interventions.
Joint pain should be treated with mechanical interventions, C
physical therapy, CBT and surgical correction
All
Bruckner 2011 [126] (4b), Gandrud 2003 [131] (4b), Martinez

2010 [125] (5a), Lacativa 2010 [127] (5a), Tilg 2008 [128] (5a),
Noguera 2003 [130] (5a), Falcini 1996 [132] (5a)
Osteoporosis should be treated to reduce pain in EB
All
Levis 2012 [129] (1a), Martinez 2010 [125] (5a)
Back pain should be addressed with standard

multi-disciplinary care
All
Chou, et al., 2007 [133] (5a)
G. Corneal abrasions are common in EB, prevention and supportive care are appropriate
Care should include general supportive and analgesic care,
protecting the eye from further damage, and topical
therapies
All
Watson, 2012 [136] (1a), Calder 2005 [138] (1a)
H. Pain in infants is as widespread as in any other age, but unique pharmacologic, developmental and physiologic issues must be accounted for
in infants with all types of EB
Assess patients as needed and prior to and after
interventions; health care workers should use validated
measures. (Grade: A)
Infants
Gibbins 2014 [139] (2a) Stevens 2014 [140] (2a), Hummel

2008 [141] (2a), Krechel 1995 [142] (2b), Lawrence 1993
[143] (2b), Manworren 2002 [144] (2a)
Sucrose solutions should be administered for mild to

moderate pain alone or as an adjunct
Young
infants
Harrison 2010 [150] (1a), Yamada 2008 [149] (1a) Cignacco

2012 [151] (2a)
Standard analgesics should be used in infants as in older

patients with careful attention to dosing and monitoring
Infants
Tremlett 2010 [153] (5a), MacDonald 2010 [154] (5b)
I. End of Life pain care is an expected part of care for EB, which in many cases is life-limiting in nature. All basic principles of palliative care apply
as they do for other terminal disease states.
Assess and manage physical, emotional and spiritual
suffering of the patient, while providing support for the
whole family
All
Craig 2007 [165] (5a), AAP 2000 [166] (5b), WHO [167] (5b)
Opioids are the cornerstone of good analgesia in this

setting. Opioid rotation may need to be considered to
improve analgesia and reduce side effects, and adjuncts
may need to be added
All
Eisenberg 2009 [174] (1a), Quigley 2010 [172] (1a), Davies

2008 [61] (4a), Bruera 1996 [171] (4b), Watterson 2005 (5b)
Consider targeted medication for neuropathic pain when

pain proves refractory to conventional therapies
All
Allegaert 2010 (5a), Saroyan 2009 (5a). Clements 1982 (5a),

Watterson 2005 [87] (5b)
Continuous subcutaneous infusion of combinations of

medication is an option when parenteral therapy is
needed in the terminal phase
All
Reymond 2003 [178] (2b), ONeil 2001 [176] (5a), Watterson

2005 [87] (5b)
Where needed, breakthrough medication can be given

B
transmucosally (oral or nasal) for rapid onset and avoidance
of the enteral route
All
Zeppetella 2009 [182] (1a)
J. A combination of environmental, cognitive-behavioral and pharmacologic therapies are available for use for EB-related pruritus, which can be a
severe symptom of the disease.
Use environmental and behavioral interventions for itch
control
All
Nischler 2008 [183] (5b), EB Nurse Website [187] (5b)
Antihistamines are recommended and can be chosen

depending upon desirability of sedating effects
All
Ahuja 2011 [188] (2b), Goutos 2010 [186] (3a)
Gabapentin, pregabalin, TCA, SNRIs and other

non-traditional antipruritics agents should be strongly
considered for itch treatment
All
Goutos 2010 [186] (3a), Ahuja 2013 [189] (2a), Murphy 2003
[197] (2a)
EB, epidermolysis bullosa; GERD, gastroesophageal reflux disease; SNRI, serotonin norepinephrine reuptake inhibitors; TCA, tricyclic antidepressant.
psychological state of heightened awareness and focused

attention, in which critical faculties are reduced and susceptibility and receptiveness to ideas are greatly enhanced
[14]. Relaxation training usually includes techniques,
such as diaphragmatic breathing, muscle relaxation and
visualization/imagery, that assist in adaptive coping via
distraction, reduced emotional arousal and activation of

the parasympathetic nervous system. While these interventions are frequently patient-focused, CBT can also include
parent/family training related to behavioral management,
reducing caregiver distress and enhancing environmental
factors necessary for positive coping [15].

Table 4 Table for judging the strength of a

recommendation [8]
Dimension
Definition
Grade of the body of evidence
High, Moderate, Low, Not Assignable
Safety/harm (side effects and

risks)
Minimal, Moderate, Serious
Health benefit to patient
Significant, Moderate, Minimal
Burden on patient to adhere to

recommendation
Low, Unable to determine, High
Cost-effectiveness to healthcare
system
Cost-effective, Inconclusive, Not

cost-effective
Directness of the evidence for

this target population
Directly relates, Some concern of

directness, Indirectly relates
Impact on morbidity/mortality
or quality of life
High, Medium, Low
Page 7 of 23
Psychological interventions are useful for the management of acute pediatric pain (see Box 1) although evidence
for their efficacy varies depending on the type of pain.
For procedure related pain, particularly needle procedures, distraction, hypnosis and CBT are effective, evidence based interventions [20-24].
In a review of non-pharmacological treatments to reduce the distress due to acute wound care in burn patients, some evidence has been shown that healthcare
provider interventions (massage and maximizing patient
control and predictability), child interventions (for example, virtual reality gaming [25] and therapist coaching
of stress management techniques [26]) are beneficial.
For postoperative pain, there is insufficient evidence for
the efficacy of most psychological interventions, but preparation, guided imagery and CBT are promising [27].
Psychological interventions for itch
As an adjunct to relaxation training, biofeedback monitors physiological functions (for example, heart rate,
muscle tension, temperature) in order to improve control of bodily processes that might ease chronic pain.
Frequently, sensors are attached to the skin by adhesive,
which is relatively contraindicated in EB. Clip on pulse
oximeter probes can be safely used in patients with EB
to track heart rate, and provide an alternative method of
biofeedback.
Efficacy of psychological interventions in chronic and acute

pain management
Psychological therapies have been shown to be effective in decreasing pain intensity and frequency in other
pediatric chronic pain conditions [16,17] with emerging evidence showing improvement in pain-related
functional disability as well [17,18]. The addition of
biofeedback to relaxation training does not necessarily
result in superior pain outcomes [17]. Modest data
support the use of CBT in adults with chronic pain
and disability [19] (see Box 1).
Box 1. Recommendations for use of cognitive
behavioral therapies in EB
Patients with EB may experience severe itch, which not

only intensifies their suffering but can also be a source
of social embarrassment secondary to the appearance of
the excoriated skin and the preoccupation with scratching in social situations. Beyond this, damage of the integrity of the skin can create a portal of entry for
systemic infections. Regardless of the underlying cause,
itch evokes the behavior of scratching that increases inflammation and stimulates nerve fibers, leading to more
itching and scratching [28]. Perpetuation of the itchscratch cycle alters the integrity of skin leading to barrier
damage. Scratching also causes undesirable changes in
skin, such as lichenification and prurigo nodule formation. Successful treatment of itch requires interruption
of this cycle. Non-pharmacological treatments, such as
CBT, hypnosis, meditation, prayer, biofeedback and eye
movement desensitization and reprocessing (EMDR),
have been used with some success in both adults and
children with conditions such as atopic dermatitis
[29]. Habit reversal is a specific behavioral intervention whereby habitual behaviors are brought into conscious awareness and specific behavioral techniques
are developed as a competing response to the urge to
itch [30,31] (see Box 1). In practice, this technique is
frequently combined with CBT and relaxation as part
of a treatment package applicable to patients of all
ages [29,32].
1. For chronic pain management use cognitive behavioral

therapy (CBT). (Grade: B)
2. For acute pain management, offer the patient distraction,
hypnosis, visualization, relaxation or other forms of CBT.
(Grade: B)
3. Consider habit reversal training, and other psychological
techniques for management of pruritus. (Grade: C)
Integrative medicine therapies
Complementary and alternative medicine (CAM) practices constitute therapies that are often requested by
patients and families for a variety of chronic pain conditions. This class of treatments includes, but is not
limited to: acupuncture, meditation, massage, herbal
preparations, yoga and chiropractic work. The evidence for therapies such as acupuncture [33], music

therapy [34], chiropractic care, or yoga [35] is modest

in the pediatric and adult pain populations, with no
specific studies in EB. Prima facie evidence would suggest that massage and chiropractic interventions might
be harmful given the skin fragility and the osteopenia
that is often seen in EB. With regard to herbal supplementation, one of the chief side effects for a number
of these preparations is bleeding, although the evidence is not clear [36]. Thus, this treatment may be
contraindicated in patients having surgery, open
wounds or a history of gastrointestinal tract bleeding.
The active ingredients in the herbal preparations may
also have interactions with any other prescribed
medication; attention to potential drug-drug interactions should be considered.
Good practice points Assessment of the suitability of
psychological therapies for EB patients experiencing
chronic and acute pain should always take into account
developmental issues including age, cognitive level and
psychopathology [37]. Include parents in behavioral
pain management interventions [38] for children and
adolescents.
Acute pain care: postoperative pain management
Introduction
As a multisystem disorder, EB causes a variety of disruptions to body systems that are amenable to surgical
intervention. While there are no controlled trials of
postoperative pain therapies in EB, general principles
of pain care apply.
Assessment
As for all patients, pain should be regularly assessed,

and then reassessed after intervention to evaluate analgesic efficacy and detect side effects. Numeric rating
scales have been shown to be effective for children of a
developmental level above eight years who can verbalize
their pain scores as well as for adults. Pain assessment
in younger or nonverbal patients can be completed
using the Face Legs Arms Cry Consolability (FLACC)
and Childrens Hospital of Eastern Ontario Pain Scale
(CHEOPS) [39,40] augmented by reports of parents or
other close family care-givers.
Systemic therapies
Analgesic treatment starts before and during surgery

and includes the use of opioids, non-steroidal antiinflammatory drugs, acetaminophen and, when appropriate for the type of surgery, regional anesthesia [41,42].
Patient controlled analgesia (PCA) technology is a safe
and useful way to deliver opioids to patents of all ages
with EB, as it is for non-EB patients (see Box 2).
Page 8 of 23
Box 2. Recommendations for acute pain care in EB
1. Basic perioperative pain assessment and treatments should be

used as for non-EB patients, with modification. (Grade: A)
2. Transmucosal (including intranasal fentanyl and trans buccal
opioids) should be considered for short procedures and pain
of brief duration when intravenous and enteral routes are
unavailable. (Grade: B)
3. Perioperative opioid use must take preoperative exposure
into consideration, with appropriate dose increases to
account for tolerance. (Grade: B)
4. Regional anesthesia is appropriate for pain resulting from a
number of major surgeries. Dressing of catheters must be
non-adhesive and monitored carefully. (Grade: C)
In the postoperative period, EB patients may be slow to

resume oral intake, especially after oropharyngeal procedures, such as esophageal dilatation or dental rehabilitation. For patients lacking gastrostomy tubes, intravenous
analgesia may be required. Intravenous analgesia should be
multimodal and may include opioids (for example, morphine or hydromorphone), nonsteroidal anti-inflammatory
drugs (NSAIDS; when postoperative bleeding is not a
risk and renal function is normal (for example, ketorolac))
and acetaminophen (enteral or intravenous). Given the
high rate of superficial bleeding from skin wounds,
cyclooxygenase-2 inhibitors may have a role to play, given
they have prothrombotic features in some studies [43].
Due to the risk of blister formation with rectal manipulation, there is controversy regarding whether the rectal
route of administration may be used in EB patients [44].
Intranasal opioids can be effective for short-term treatment, if other routes are not available [45-47], and may be
particularly helpful for procedures of short duration
when rapid-acting analgesia is desired in the absence
of intravenous access. Oral disintegrating and transbuccal formulations may be helpful as well, although
they presume intact mucosa, which may not be applicable (see Box 2).
Patients with prolonged postoperative pain because of
extensive surgery may benefit from the use of opioidbased PCA with dose adjustments that take into consideration prior opioid use. While no EB-specific literature
exists, this modality is standard treatment in many centers for patients old enough to understand the concept
(typically seven years of age or older). Activation of the
dosing button may be limited by pseudosyndactyly, so
use should be determined on a case-by-case basis. PCAby-proxy (dose administered by a nurse or designated
family member) is practiced in some pediatric centers

and may be an alternative approach to PCA dosing for

children.
Preoperative tolerance
The preoperative pain status of the patient should be

taken into consideration when choosing opioid dose,
both intra- and post-operatively. Many EB patients have
recurring acute and/or chronic pain and may be taking
opioids daily, either prior to bathing/dressing changes or
for ongoing pain. These patients require increased doses of
opioids for adequate analgesic effect, due to the development of tolerance. Their usual daily opioid intake should
be considered the baseline opioid dose to which the postoperative analgesia should be added (see Box 2). Drug
pharmacokinetics may be altered in patients chronically
exposed to sedatives and opioids. Flexibility in dosing, review of prior anesthetic records and discussion with the
patient or family can aid appropriate dosing.
Page 9 of 23
Non-pharmacologic therapies
Non-pharmacologic techniques should also be employed

in combination with the pharmacologic techniques listed
above. These include, but are not limited to, distraction
(music, reading, video games and movies), visualization,
imagery/virtual reality and breathing techniques (see Efficacy of Psychological Interventions in Chronic and
Acute Pain Management, above and Box 1). Effective
approaches used in the past should be discussed with the
patient or parents and their use supported whenever
possible.
Good practice points Postoperative pain can be managed as for other patients in the same setting, with modifications to account for the ability to self-administer
medications, prior drug exposure, and the condition of
the skin at potential regional anesthesia injection/catheter
sites.
Regional anesthesia
Chronic and recurrent pain care
Some common procedures (and the corresponding regional

anesthesia technique used) in EB patients include: fundoplication (epidural) [48-50], hand and foot surgery (peripheral
nerve block, either single shot or continuous peripheral
nerve catheter infusion following bolus injection) and hand
surgery (both axillary and infraclavicular approaches have
been used for brachial plexus block) [51,52].
Regional anesthesia techniques should be modified in
patients with EB to minimize damage to the skin. Skin
preparation may be performed by pouring prep solution
(povidone-iodine or chlorhexidine) on the site without
rubbing, then blotting and allowing the solution to dry.
Ultrasound guidance can be used for peripheral nerve
blocks with generous use of gel to minimize skin abrasion when moving the probe. When a catheter is placed
(epidural or peripheral nerve), it may be tunnelled subcutaneously if desired [53] then secured to the skin
using silicone-based tapes and dressings (MepitacW,
MepitelW, MepilexW) or other soft non-adhesive dressings. Adhesive dressings and adhesive adjuncts should
be avoided. If there is any doubt about the safety of
using a dressing, it should be tested on a small area of
skin with patient or parental consent. With local infection
being a relative contraindication to regional anesthesia,
examination of the skin overlying the point of entry is
mandatory prior to attempting a catheter placement. If leaving a catheter in the epidural space is undesirable, then a
single injection of a long-acting form of opioid (DepoDurW)
may be a good option when available [54,55], although
monitoring is important due to risk of hypoventilation
[56]. Lidocaine infiltration may be used by dentists/
oral surgeons when extractions are necessary, but care
must be taken when injecting to avoid mucosal blister
formation (see Box 2).
EB has a large number of painful complications, some

chronic and others acute but repetitive. Care of EB involves painful interventions on a daily basis. Almost
every organ system can be affected, but the following are
the major sources of pain: skin, gastrointestinal tract,
musculoskeletal system, eyes.
Skin and wound pain
Introduction The classic presentation of EB is the development of skin wounds that are painful in their own
right, but which often become infected, heal poorly and
frequently lead to scarring. This combination makes skin
and wound pain a prominent complaint of patients with
EB.
Environmental and behavioral approaches Dressings
that are non-adhesive upon removal, such as siliconebased products, are helpful in reducing skin-trauma
pain. Different subtypes of EB and different individuals
seem to have varying dressing requirements [57]. Nutrition is important in promoting wound healing, and
anecdotally, patients with poor nutritional status have
more wounds and slower healing, which lead to increased pain. Experience suggests that attention to
good nutrition, surveillance for superficial infection
and aggressive treatment of infection reduce pain. As
discussed in the section on psychological interventions, CBT is helpful for a number of painful conditions and should be applied in EB.
Systemic approaches The pharmacological treatment of
skin and wound pain is non-specific, with no evidence in
the EB population to promote one treatment over another. NSAIDs, acetaminophen, tramadol and opioids

are used with success. Cannabinoids have some anecdotal support. Itch is a major problem (see below) that
can lead to increased scratching and subsequent development of painful wounds. Hence, managing pruritus is
important to prevent wound-related pain.
Many patients with severe types of EB use longacting opioid preparations to provide a basal comfort
level. Of note, there are no clear guidelines that longacting opioids are preferable to use of intermittent
opioids for non-cancer pain [58], although there is
modest evidence for opioid use, in general, for noncancer pain in adults [58,59]. Individualization of therapy is recommended.
Regular and frequent dosing of opioids is common
and merits special attention. Regardless of the opioid
chosen, chronic use of opioids may have endocrinologic effects, such as hypogonadism [60]. Monitoring
should be considered, especially given the propensity
for osteopenia and delayed puberty in adolescents
and young adults with EB. In the absence of data, the
use of opioids is recommended as clinically indicated
(see Box 3).
Box 3. Recommendations for wound pain treatment
1. Maintain optimal nutrition and mobility and treat infections

as indicated (Grade: D)
2. Consider topical therapies for pain (Grade: C)
3. Systemic pharmacologic therapy should be adapted to treat
both acute and chronic forms of skin pain. (Grade: B)
4. Monitor potential long-term complications of chronically
administered medications. (Grade: C)
Methadone merits particular consideration. Dose titration can be unpredictable due to long and variable halflife as well as to saturable plasma protein binding [61].
The long and variable half-life, as well as the risk of
methadone-induced prolonged QT syndrome [62,63],
mandates care in its use alone and with other drugs that
may also prolong the QT interval. Guidelines on electrocardiographic screening are limited [64] (especially for
adult patients of smaller stature and children). Given the
risk of prolonged QT and methadones complex and variable pharmacokinetics, it is recommended that methadone only be prescribed by practitioners with experience
evaluating and monitoring its use [65]. Methadone use is,
therefore, best done with input from a pain management
and/or palliative care specialist.
Among the common side effects of opioids, constipation [66] and pruritus are particularly significant. Both
Page 10 of 23
are significant baseline problems in EB and the reader is

referred to the sections on gastrointestinal pain and
pruritus.
The pain of extensive wounds has a quality suggestive
of neuropathic pain; both are often described as burning in quality. There is evidence supporting the use of
gabapentin for neuropathic pain in other conditions
[67]. Medications such as tricyclic antidepressants and
gabapentin have shown anecdotal success in EB skin
pain in a child [68], as well as for adult patients with
acute skin pain due to burns [69]. The potential for tricyclic antidepressants to prolong the QT interval means
that caution should be taken using this class of medications in RDEB patients, who are at risk for developing
cardiomyopathy [70], as a lethal outcome in this setting
has been reported [71].
Topical approaches For localized wounds, topical lidocaine jelly (2% concentration) has been used anecdotally.
Morphine mixed in hydrogel formulations has been used
in different types of localized painful wounds [72,73] but
has only limited anecdotal experience in EB wounds [74]
(see Box 3). Use of these medication vehicles raises
questions of absorption and systemic effects that require
further investigation before full recommendations can be
made. Limited anecdotal evidence supports the use of
keratinocyte hydrogel dressings for poorly healing wounds
and RDEB [75].
Blood draws and intravenous access as well as the
need for skin biopsies are minor technical procedures
that can be very distressing, especially for children. Topical anesthetics are commonly used in non-EB populations with good effect. Amethocaine appears to be more
effective than a eutectic mixture of local anesthetics
(EMLAW) [76]. These may have a role when applied to
intact skin, but cannot be recommended for use on
wounds due to unknown rate and extent of absorption
of lidocaine. Blistering as a localized allergic reaction
to EMLAW (or its contents) has been rarely observed,
indicating caution in its use even on intact skin. Lidocaine injected with a small gauge needle is a standard
approach to superficial analgesia in all age groups.
Additionally, it is recommended that bicarbonate be
added to buffer the pH of the lidocaine to reduce the
pain of injection [77]. As noted above, CBT (for example, distraction and relaxation) is effective in the
acute pain setting [21] and should be employed whenever possible in conjunction with medication management (see Box 1).
Good practice points Prevention and rapid healing of
wounds through non-adherent dressings, optimal nutrition and infection control are priorities.

Bathing and dressing changes
Introduction Bathing and bandage changes are a source of

significant recurrent pain and anxiety for patients with EB.
Environmental treatment Oatmeal and salt have been

added to bath water to reduce the pain of immersion
[78]. The former may have anti-pruritic, cleansing and
protective properties for dermatologic conditions in general [79] that may be similarly effective in EB. Salt is
added to make the water isotonic, which has anecdotal
support from many families of patients with EB including preliminary survey data from EB families [80]. Isotonic saline (0.9% NaCl) is 9 grams of salt/1 liter of
water; total amount of salt varying according to the desired
water volume. Bleach and vinegar are anecdotally helpful
in drying the skin and reducing bacterial colonization,
which some patients find comforting while others report
increased pain at the wound sites. The salt water does not
require plain water rinse, whereas vinegar and bleach baths
require rinsing to reduce the risk of itch. Many patients
elect to reduce the frequency of bathing as a simple measure to minimize bath-related pain. Anecdotally, starting
the bath by immersing the patient still in his/her bandages
can ease the transition into the water and help reduce the
pain of removing the dressings. Other patients find drafts
from heating and cooling systems to be painful on open
wounds, so attention to general environmental factors is
recommended (see Box 4).
Box 4. Recommendations for bathing and dressing

change pain treatment
1. Anxiolytics and analgesics should be used for procedural pain

and fear. Care must be taken when combining such
medications due to cumulative sedative effects (Grade: B).
2. Cognitive behavioral techniques should be implemented as
the child becomes old enough to use them effectively.
Specifically, distraction should be used for younger children
(Grade: B).
3. Environmental comfort measures are recommended; these
include adding salt to the water to make it isotonic and
keeping the room warm (Grade: B).
Analgesics Analgesics used by patients with EB have included enteral opioids, NSAIDs and acetaminophen.
The nasal route may permit administration of medications when intravenous access is absent [81]. Fentanyl
works well by this route for non-EB patients in the
Page 11 of 23
perioperative setting [45], for breakthrough cancer pain

(see section on Breakthrough pain medication at the end
of life) and has been used for acute pain management in
the emergency department with success [46]. Butorphanol
is a mixed agonistantagonist that can be used via the intranasal route and is effective both for pain (for example,
dental postoperative pain [47]) as well as for opioidinduced pruritus. Fixed dose spray is available for outpatient use in the United States, which limits the ability to
adjust for patient size. Timing of medication administration should be adjusted to match expected peak analgesia
with anticipated peak pain (see Box 4).
Ketamine can be administered enterally for wound care
pain, for which there are data from adult and pediatric
burn populations [82,83] but not for EB patients. The IV
form of ketamine given orally has been used with variable
success for other chronic pain conditions [84] as well as in
cancer patients [85] and in pediatric palliative care [86].
Inhaled nitrous oxide has been suggested for pediatric
wound care in EB in some texts and review articles
[44,87], but its use in EB patients has not been studied
or reported. Nitrous oxide has been used for painful procedures in other settings [88] and is available in both
fixed 50:50 and variable combinations with oxygen. Depending on the delivery system (mouth piece, face mask,
or nasal mask) concerns arise about environmental pollution and exposure of health care personnel [89]. In the
absence of evidence of efficacy, concern must be raised
about repeated use for wound care or dressing changes
because of longstanding evidence of megaloblastic bone
marrow changes and neurologic abnormalities due to inhibition of methionine synthase and cobalamin activity
with repeated exposure to nitrous oxide [90,91].
Anxiolysis The pain caused by baths and dressing changes
is commonly cited by families as generating anxiety in the
patient, which in turn is stressful for the caregiver. Medications used for acute anxiolysis in this population include
midazolam, diazepam and lorazepam and are considered
good treatment for acute anxiety in other populations (for
example, children for dental procedures, [92,93]; prior to
adult burn procedures [94]). In addition to anxiolysis, the
pre-procedural use of benzodiazepines offers the possibility
of anterograde amnesia which may prevent the development of increased anxiety with repeated procedures. When
using benzodiazepines in combination with opioids, care
must be taken to avoid over sedation (see Box 4). As response to each medication will have individual variation,
dose adjustments should be made carefully and preferably one drug at a time, when more than one is being
administered.
Other behavioral comfort measures In addition to
medication management, recommendations from caregivers

include preparing all materials ahead of bandage removal to reduce the amount of time wounds are exposed to air. Involving children in the process at as
early an age as possible helps them to develop a sense
of control. Maintaining room temperature at a moderately warm level has also been recommended. CBT can
be applied to treating the anxiety and pain associated
with bathing and bandage changes (see section on psychological approaches, above).
Good practice points Bathing and dressing changes are
recurrent sources of both pain and anxiety. Therapy
should focus on both symptoms, using environmental,
psychological and pharmacologic approaches.
Pain related to the gastrointestinal tract
Introduction Gastrointestinal complications are common in children and adults with EB with specific complications linked to different subtypes [95-97].
Upper gastrointestinal tract
Topical treatments Oral ulceration, blistering and mucositis are the most frequent gastrointestinal complications in patients with EB [98]. While oral ulceration
can occur in all types of EB, it is most common and
problematic in patients with the severe types of this
disease. Oral ulceration can be extremely painful and
lead to difficulties in feeding and maintaining dental
hygiene. Apart from oral analgesics, topical preparations
are available. Sucralfate suspension has been used to
prevent and manage oral blisters in five children, 6- to
11-years-old, with RDEB when applied four times a day
for six months [99]. The number of blisters reduced
within three weeks and pain reduced within one week
(see Box 5).
Box 5. Recommendations for gastrointestinal pain

treatment
1. Topical treatments are recommended for oral and perianal

pain. (Grade: C)
2. Therapy should be directed to manage gastroesophageal
reflux and esophageal strictures using standard treatments.
(Grade: C)
Page 12 of 23
Polyvinylpyrrolidone-sodium hyaluronate gel (GelclairW)

either used as a mouth rinse or applied directly to a
mouth lesion in children, has been used anecdotally in EB.
Secondary evidence comes from two recent reviews which
showed that GelclairW may be useful as an adjunctive therapy in decreasing the painful lesions of oral mucositis in
cancer patients [100,101]. Chlorhexidine gluconate and
benzydamine hydrochloride mouth spray is used regularly
in EB patients at the London centers with reported benefit
but has not been evaluated systematically. Secondary
evidence for the potential efficacy of this intervention
exists for treating the pain of acute viral pharyngitis in
adults [102].
Gastroesophageal reflux Patients with EB are at high
risk for gastroesophageal reflux disease (GERD) - especially
infants with generalized EBS, JEB and patients with severe
generalized RDEB who can develop esophagitis [95]. While
children with GERD may not complain of dyspeptic symptoms until they are older, crying and sleep disturbance are
commonly associated with this symptom. Management is
guided by standard treatment in non-EB patients, and
may involve treating the reflux with antacids, histamine H2-blockers and proton pump inhibitors and,
rarely, surgery [103,104] (see Box 5).
Esophageal strictures Esophageal stricture formation
and dysphagia are most common in patients with severe
generalized RDEB with a cumulative risk of developing
strictures or stenosis rising steadily from 6.73% at age
1 year to 94.72% at age 45 years [105]. However, strictures
can also be seen in other subtypes of EB including Kindler
syndrome [106]. Dysphagia and delayed progression of
food through the stricture can present with retrosternal
chest pain. Esophageal strictures, if symptomatic, require
treatment with a fluoroscopically guided balloon dilatation
with peri- and post-operative steroids administered to reduce the recurrent stenosis rate [107-109] (see Box 5).
Acute symptoms can respond temporarily to oral dexamethasone or nebulized budesonide, based on anecdotal
evidence. A recent case report examined the use of daily
oral viscous budesonide therapy (0.5 mg/2 mL budesonide
nebulizer solution mixed with 5 g of sucralose and maltodextrin) in two children with RDEB who had recurrent
proximal esophageal strictures [110]. Both children had a
reduction in the rate of stricture formation and symptoms
of dysphagia.
3. Constipation should be addressed nutritionally, with

hydration and addition of fiber in the diet to keep stool soft,
with stool softeners and by minimizing medication-induced
dysmotility. (Grade: C)
Lower gastrointestinal tract
Constipation Constipation has been shown to be present

in 35% of children with all types of EB [95] and can cause
abdominal pain and pain on defecation as well as lead to
perianal trauma. A case of colonic perforation and early

death resulting from severe constipation in DEB has been

described [111]. Chronic perianal pain during defecation
can produce stool withholding behavior which exacerbates
constipation. Chronic opioid use may contribute to poor
bowel motility. First line management is prevention
with dietary manipulation; however, patients with severe
types of EB often require the regular use of a laxative
(see Box 5). Polyethylene glycol is effective clinically in
treating constipation in children and adults with EB,
with empiric evidence of efficacy in adult [112] and
pediatric [113] non-EB cohorts.
Colitis A subgroup of children with RDEB may develop
colitis, presenting with abdominal pain and other symptoms [95,114]. Dietary restriction and anti-inflammatory
drugs, such as sulfasalazine, have been used but with
variable effects on controlling the colitis [95].
Perianal pain Perianal blistering and ulceration is common and debilitating in children and adults with severe
types of EB. Topically, sucralfate has been shown to be superior to petroleum jelly in facilitating anal fistulotomy
healing and lessening wound pain [115]. Sucralfate suspension has also been used to lessen the pain of oral and
genital ulceration in patients with Behcets disease [116].
Anecdotally, topical sucralfate combined with Cavilon
(an alcohol-free liquid barrier film that dries quickly to
form a breathable, transparent coating on the skin, containing hexamethyldisiloxane, isooctane, acrylate terpolymer, polyphenylmethylsiloxane) appears to improve pain
in perianal lesions of some patients with EB. Non-surgical
treatment is of small benefit for both pain and healing of
chronic anal fissures [117], with recommendations of topical diltiazem and glyceryl trinitrate followed by surgery if
needed in adults [118]. No data on anal fissure treatment
in EB patients exist (see Box 5).
Good practice points EB affects the gastrointestinal
tract in its entirety. Pain that originates from ulcerative
lesions may respond to topical therapy. GERD and
esophageal strictures have nutritional as well as comfort
implications and should be addressed promptly when
found. Maintaining good bowel habits and reducing iatrogenic causes of constipation are crucial.
Musculoskeletal pain
Introduction Musculoskeletal complications are common and frequently painful for patients with EB. These
conditions include pseudosyndactyly, osteopenia, back
pain, fractures and occasional co-morbid rheumatologic
disorders.
Joint pain Pseudosyndactyly affects hands, feet, ankles
and wrists. Painful hyperkeratotic lesions develop on the
Page 13 of 23
soles of patients with EBS. Occupational therapy approaches can improve function and decrease pain via use
of adaptive equipment and specially designed orthotics and
clothing. Physical and occupational therapy play crucial
roles in encouraging patient mobility. For weight-bearing
patients, careful attention to footwear, nails, orthotics and
hyperkeratosis management are important aspects of pain
care [119]. Referring patients to programs to maintain or
regain strength, to prevent or minimize joint contractures,
and to optimize mobility is recommended based on anecdotal evidence (see Box 6). Coping skills training and activity pacing can enhance effectiveness of therapy [120].
Surgical intervention has had some success in increasing
mobility and reducing pain [121]. EB patients can also have
inflammatory arthritis [122,123]; appropriate imaging can
be helpful in determining inflammatory causes of pain.
Given that inflammatory markers are usually elevated in
EB patients, these markers alone are not likely to be useful
to diagnose joint pathology.
Box 6. Recommendations for musculoskeletal pain
treatment
1. Joint pain should be treated with mechanical interventions,

physical therapy, cognitive behavioral therapy and surgical
correction (Grade: C).
2. Osteoporosis should be treated to reduce pain in EB (Grade: D).
3. Back pain should be addressed with standard multi-disciplinary
care (Grade: C).
Bone pain Osteopenia, osteoporosis and fractures are

now well recognized and commonly seen in patients with
the severest types of EB [124-126], as a cause of bone and
joint pain. The causes are multifactorial and include reduced mobility, delayed puberty, limited exposure of the
skin to sunlight, inadequate nutritional intake for metabolic requirements and chronic inflammation. Chronic inflammation causes increased osteoclast activity [127,128].
As a consequence of the osteoporosis, a significant
proportion of patients develop fractures. The incidence
of vertebral fractures in patients with RDEB is unknown,
but may be underestimated due to the fact that fractures
of the lumbar and thoracic spine may be clinically silent,
or present without overt or localized back pain on palpation [125]. Anecdotally, however, some patients can
present with back pain, in which case a high index of
suspicion should be maintained. Treatment of osteoporosis and derivative pain is based upon standard treatment of osteoporosis in non-EB patients, which relies on
vitamin D and calcium supplementation, exercise and
bisphosphonate treatment [129] (see Box 6).

Anecdotally, bisphosphonates have been found useful

in treating patients with evidence of osteoporosis without fracture. Bisphosphonates appear to improve fractures
on annual X-rays and lead to a noticeable improvement in
pain. Indirect support for the use of bisphosphonates
comes from its use in rheumatologic and other pediatric
conditions, associated with osteopenia [130,131] and resolution of back pain [131,132], but efficacy specifically in
patients with EB has not been formally studied.
Back pain Older patients with EB can have back pain.
Beyond osteopenia-related issues, biomechanical causes
can be involved. Foot blisters and painful hyperkeratosis
can cause abnormal gait and compensatory postures.
Further, impaired mobility can add a myofascial component to pain. Management of back pain includes optimal
foot care, assessment of primary and secondary mechanical factors, evaluation and treatment of osteopenia and
fractures, physical therapy, standard analgesics and CBT
interventions. Back pain treatment in the EB population
is extrapolated from basic principles recommended for
the general population [133], for lack of EB-specific
evidence (see Box 6).
NSAIDs are routinely used for bone and joint pain of
a variety of types and are appropriate for these types of
pain in EB. Care should be taken to monitor for side effects, and the cyclooxygenase-2 inhibitors may be useful
in those patients who experience improved pain control
but note increasing blood loss from wounds, or who
have gastrointestinal upset with standard NSAIDs. Acetaminophen does not affect bleeding and can be useful.
Tramadol and opioids are also useful for more severe
pain. Some prefer use of long-acting opioid preparations,
with methadone being the only one available in liquid
form. Limitations in methadone use are discussed in
sub-section on systemic approaches under Skin and
Wound Pain.
Good practice points Bone health should be optimized
with calcium and vitamin D supplements as needed,
maintenance of maximum mobility, minimization of joint
deformity and monitoring for/treatment of pubertal delay.
Routine screening for bone mineral density may be useful
to ascertain cases of osteopenia before they progress to
osteoporosis and fractures. Care must be taken not to
overlook inflammatory joint disease, as pain secondary
to this will respond to disease modifying therapy. Multidisciplinary treatment modalities are helpful in addressing back pain and apply to such pain in the EB
population as well.
Eye pain
Ophthalmologic involvement is pervasive in EB [134,135].

Eye pain is often caused by corneal abrasions. Comfort
Page 14 of 23
measures such as avoiding bright light (a natural reaction

to the photophobia that results from the trauma), lubricating eye drops, NSAIDs and antibiotic drops have been
used. Evidence for these treatments for recurrent corneal
abrasions of other etiologies is modest [136]. The use of
eye patches in non-EB patients does not aid pain relief
and, therefore, is not recommended for use in EB patients
either [137]. There is some evidence that topical NSAIDs
provide analgesia for acute, traumatic corneal abrasions
[138] (see Box 7).
Box 7. Recommendations for eye pain treatment
1. Care should include general supportive and analgesic care,

protecting the eye from further damage and topical therapies
(Grade: C).
Good practice points Corneal abrasions are painful and

common in EB; prevention and supportive care are
appropriate.
Special Topics
Pain care in infants with EB
Introduction In the severe forms of EB, pain starts immediately, and great care needs to be taken in most
of the activities of daily living. Infants with EB require
careful attention to environmental factors at a higher
level than for older children but otherwise can receive pain care using guidelines for specific types of
discomfort.
Pain assessment Pain assessment should be completed
on all neonates with EB at regular intervals and as
needed (see Box 8). A valid neonatal pain scale should
be used, considering both physiologic and behavioral
measures. Some examples include: the Premature Infant
Pain Profile (PIPP) [139,140], the Neonatal Pain Agitation and Sedation Scale (N-PASS) [141], the Crying, Requires oxygen, Increased vital signs, Expression and Sleepless
pain scale (CRIES) [142], and the Neonatal Infant Pain Scale
(NIPS) [143]. The Face Legs Arms Cry Consolability
(FLACC) scale is recommended for infants between 1 to
12 months [144]. These pain scales have been validated
for use by nurses, although training could be generalized
to non-nurse care givers and family members. Pain should
be reassessed frequently during and after interventions
and until comfort is achieved based on a combination of
one of the above scales and clinical judgment. Analgesic
interventions should match degree or level of pain. Of
note, infants, especially neonates, seem to be a higher risk

for respiratory compromise [145,146] due to reduced

clearance of opioids in infants younger than two months
[147,148]. Therefore, careful clinical and cardiopulmonary
monitoring is crucial when providing opioids to this population (see Box 8).
Box 8. Recommendations for infant pain care
1. Assess patients as needed and prior to and after

interventions; health care workers should use validated
measures. (Grade: A)
2. Sucrose solutions should be administered for mild to
moderate pain alone or as an adjunct. (Grade: B)
3. Standard analgesics should be used in infants as in older
patients with careful attention to dosing and monitoring.
(Grade: B)
Procedural pain As for older patients, procedures are

one of the major sources of pain for infants with EB.
Wound care specifically requires a multidisciplinary team
approach to ensure consistent and optimized pain control.
There is evidence that a variety of pharmacologic and
non-pharmacologic interventions are helpful in both
term and pre-term infants [149]. Therefore, pain management interventions should precede all scheduled
painful procedures, such as dressing changes, bathing
and venipuncture. The range of analgesics and the routes
by which they can be administered are the same as for
older patients. Oral sucrose is an analgesic unique to
young infants and can be used alone for mild pain (for example, immunization pain [150]) or in conjunction with
other analgesics as well as physical and environmental interventions for more severe acute pain [40,151].
Bathing and dressing changes To maintain appropriate
moisture levels and facilitate the healing of wounds,
dressings should be non-adherent as for older patients
and appropriate in size. Infected wounds will require
more frequent dressing changes [57,152]. Changing
dressings one limb at a time is advocated in infants, to
reduce the likelihood of having the skin rubbed off the
opposite limb by feet kicking together, causing new,
painful lesions (see Box 8). This approach also decreases
the chance of bacterial spread from a colonized wound to
an uncontaminated area [57,78]. For baths, adding salt to
the water is recommended as for older patients (see subsection on environmental treatment under Bathing and
Dressing Changes).
In addition to environmental adjustments, many infants
will require analgesics with bath and dressing changes.
Page 15 of 23
NSAIDs, acetaminophen and opioids are all used, as for

older patients (see Section Bathing and Dressing Changes)
(see Box 8). Codeine is not recommended, when alternatives are available, as neonates lack the capacity to
metabolize the drug into active metabolites, and clinical
responses are highly variable at all ages, due to polymorphisms in codeines metabolic pathway [153,154].
Severely affected hospitalized infants Severely affected
newborns with deep tissue damage may require extensive pharmacologic support to achieve a level of comfort
(see Box 8). These infants may require around the clock
or continuous infusion of opioids and an adjuvant. A
transition to methadone for better steady state levels
should be considered (refer to sub-section on systemic
approaches under Skin and Wound Pain) for caveats
about methadone use). A case study has shown effective
pain control in an infant with severe chronic pain (and
possibly pruritus) when treated with gabapentin [155].
Patients receiving frequent opioid treatment may require
extra care in avoiding opioid-induced constipation and
in maintaining adequate caloric intake.
Oral ketamine has been used to supplement opioids
when pain associated with dressing changes is severe
[156]. Use of ketamine raises concerns due to findings of
adverse neurodevelopmental effects in young animals
who received prolonged intravenous infusions of ketamine [157]. However, these effects are not known to
occur in human infants and are unlikely to occur with
small doses administered at intervals.
Good practice points Infants benefit from the same
range of analgesics as older patients. They can uniquely
benefit from oral sucrose for brief painful episodes.
Careful monitoring is crucial in infants receiving sedating medications. Babies with EB and their parents benefit from close physical contact like any other families.
Holding and cuddling can be done safely, with scrupulous attention to lifting and handling in order to prevent
new lesions and pain.
End of life pain care
Introduction The epidemiology of death in EB varies by

type [158], but is not limited to dermatologic causes. Patients with JEB, generalized severe type are at greatest
risk of fatality early in life from a range of causes
[159,160]. Persons with RDEB may succumb in early to
mid-adulthood from multiple causes [161-163] whereas
patients with generalized types of EB simplex are at risk
of laryngotracheal complications [164].
The palliative approach to pain experienced by individuals who are facing life-threatening illness addresses the
physical, emotional and spiritual suffering of the patient

and includes support for the whole family [165-167]

(see Box 9). Squamous cell carcinoma is frequently diagnosed in patients with severe subtypes [168] and can
present challenges typical of cancer-related pain when
it metastasizes. The World Health Organization ladder
approach to pain care for those patients with cancer
and other persistent illnesses recommends a two-step
ladder as a framework for pain care [169].
Box 9. Recommendations for end of life pain

treatment
1. Assess and manage physical, emotional and spiritual suffering

of the patient, while providing support for the whole family.
(Grade: A)
2. Opioids are the cornerstone of good analgesia in this setting.
Opioid rotation may need to be considered to improve
analgesia and reduce side effects, and adjuncts may need to
be added. (Grade: B)
3. Consider targeted medication for neuropathic pain or when
pain proves refractory to convention therapies. (Grade: D)
4. Continuous subcutaneous infusion of medication is an option
when parenteral therapy is needed in the terminal phase.
(Grade: C)
5. Where needed, breakthrough medication can be given
transmucosally (oral or nasal) for rapid onset and avoidance
of the enteral route. (Grade: B)
Opioids Opioids have a role in EB pain management, as

previously indicated in these guidelines (see Box 9). Patients in the palliative phase of their illness may be given
an oral opioid sustained release medication [170]. Opioids should be titrated against pain and side effects, with
differences in approach needed depending on issues
such as opioid tolerance and rate of development of new
pain problems [170]. However, if appropriate opioid increases are not effective, it is important to consider
pharmacologic tolerance, poor absorption and neuropathic pain. Tolerance can be addressed by rotating the
opioid to capitalize upon incomplete cross-tolerance
[171,172]. In the face of poor absorption, parenteral
therapy may be needed (see below). If neuropathic pain
is suspected, methadone may be an option to consider.
It has N-methyl-D-aspartate (NMDA) antagonist action
in addition to mu-agonist properties common to standard opioids, and can be beneficial for neuropathic pain
[173] and does not rely on renal excretion [61], which
may be reduced in the palliative phase of EB [87].
Page 16 of 23
Although a recent meta-analysis could not establish differences in efficacy among types of opioids for neuropathic pain, it was determined that intermediate term
(weeks to months) use of opioids for neuropathic pain
may be helpful [174]. Cautions in the use of methadone
are discussed in the sub-section on systemic approaches
under Skin and Wound Pain.
Adjunctive measures for neuropathic pain Many EB
patients will have been treated with adjunctive agents
such as amitriptyline or gabapentin earlier in their illness, often with good effect [87,155]. These both may
take a period of time to achieve full analgesic effect and
usually need to be given by the enteral route. Ketamine is
more rapidly effective and can be given orally [84-86,175]
or used subcutaneously (see below). It should be noted
that when ketamine by-passes hepatic first pass metabolism, the relative proportion of norketamine is reduced and
the patient may experience more sedation and hallucinations and less analgesia for a given dose [175]. Other
options for addressing neuropathic pain (see Box 9) in
terminal care include opioid rotation to methadone
(see above), which can also be included in a subcutaneous infusion (see below).
Infusions and issues of drug delivery Parenteral administration of analgesia may be needed in the palliative
phase, when ability to take enteral medications is no longer an option or if rapid escalation of therapy is needed.
There has been an historic reluctance to use continuous
subcutaneous infusions, due to the fear of precipitating
further blistering. However, subcutaneous infusions have
been reported to be tolerated in the final days of life in
an adult EB patient [176] (see Box 9).
In non-EB patients with cancer pain, the subcutaneous
route of morphine is effective to a similar degree as the
intravenous [177]. Other alternatives, such as adherent
transdermal delivery systems, need regular removal and
replacement. Repeated subcutaneous/intramuscular injections are very frightening for children, as are attempts
to obtain IV access. Alternatively, sites of subcutaneous
needle insertion last reasonably well [87,177]. If subcutaneous sites do become inflamed, some benefit has been
shown from adding low dose dexamethasone to the infusion [178], although this has not been used to our knowledge in children with EB.
Breakthrough pain medication at the end of life Even
when good baseline pain relief has been achieved, most
patients will require occasional breakthrough doses of
analgesia. Uniformly effective breakthrough dosing protocols have not been determined for children with EB at
end of life, although there are general recommendations

from several international sources [169,179] and data to

support the use of up to 20% of total daily opioid consumption [180,181] in adults with cancer. In general, a
short-acting, immediate release form of opioid should be
given at approximately 10% to 15% of the total background opioid dose of the previous 24 hours. If rescue
dosing is used frequently and consistently, then the
baseline opioid dosing needs to be increased. Individual
patient factors should be taken into consideration (including prior opioid exposure, renal and hepatic function, other medication use) and consultation with an
expert in pain management and/or palliative care is recommended. The same principle is recommended for
opioids given via all routes of administration. When very
rapid onset is needed, transmucosal administration of
opioids may be preferable (see Box 9). Commercially
available transmucosal preparations of fentanyl are available in doses likely to be suitable for older children and
adults. Evidence supports the use of transbuccal fentanyl
for breakthrough pain in cancer patients [182]. An additional benefit of fentanyl is that it is not dependent on
renal excretion. In some centers, the injectable formulations of morphine or diamorphine have been used buccally at around a third of the standard enteral dose
(equivalent to the intravenous dose), allowing more
flexibility of dosing. It is also important to remember
that extreme anxiety may confound pain perception or
expression and that there may be benefit in offering additional doses of buccal midazolam where this is felt to be
a significant factor. Therapy should be targeted at specific symptoms whenever possible, although combination therapy is not unusual. Breakthrough analgesia
should be offered in the face of unexplained agitation in
case of undiagnosed pain, after which medication for
primary agitation/anxiety may be considered. While it is
likely that both of these would cause a degree of sedation at higher doses, this should not be the primary aim
of treatment.
Good practice points Palliative pain care is an expected
part of care for EB, which in many cases is life-limiting
in nature. All basic principles of palliative care apply as
they do for other terminal disease states.
Pruritus
Introduction Itch is a prominent, debilitating and damaging symptom for children with EB, but the mechanisms which lead to the manifestation of pruritus are
poorly understood [183]. Promising new insights into
the causes and potential treatments of chronic itch in
animal models [184], in human chronic itch generally
[185] and in recovering burn patients [186] may hold
potential for application in the EB population.
Page 17 of 23
Non-pharmacological approaches Multiple environmental and behavioral approaches to address itch have been
suggested [183,187] and include: prevention of dry skin
(systemic hydration and emollients), gentle debridement
of dry/dead/crusted skin, prevention and treatment of skin
wound infection; maintaining/supporting the healing
process by attention to anemia and nutritional status,
limiting damage to the skin by avoiding shear forces
imposed by scratching (short nails, occlusive barriers,
patting rather than pulling or tearing at a site), avoiding overheating and using measures to keep the body
cool (see Box 10). CBT is useful to reduce habitual
scratching behaviors (see section on psychological approaches). It is important to avoid and treat secondary
causes when present (such as drugs, environmental itch
triggers, underlying co-morbidities). Opioid-induced itch
in EB can be a problem and a difficult side effect to balance against the desired analgesia; opioid rotation may be
helpful.
Box 10. Recommendations for itch treatment
1. Use environmental and behavioral interventions for itch

control. (Grade: C)
2. Antihistamines are recommended and can be chosen
depending upon desirability of sedating effects. (Grade: D)
3. Gabapentin, pregabalin, TCA, serotonin norepinephrine
reuptake inhibitors (SNRIs) and other non-traditional
antipruritic agents should be strongly considered for itch
treatment. (Grade: C)
Pharmacological therapies Pharmacological therapies

include traditional oral antihistaminic medications (see
Box 10). Some patients prefer sedating formulations at
bedtime (for example, diphenhydramine, hydroxyzine,
chlorpheniramine) and others non-sedating preparations
during the day (for example, cetirizine, loratadine and
fexofenadine). Efficacy is variable and recommendations
are based on anecdotal experience for lack of good evidence in EB and other dermatologic conditions. Centrally
acting medications, such as gabapentin and pregabalin,
have evidence for efficacy from the burn literature
[186,188,189] and may have application in EB. Many of
these medications have also been used successfully for
neuropathic pain (see sub-section on adjunctive measures for neuropathic pain under End of Life Pain).
Antidepressants with nortriptyline re-uptake inhibitory
actions have been used for various pruritic conditions
with some evidence for efficacy, with mirtazapine showing

promise [190-193]. Low-dose cyclosporine has been used

in a single case of dominant dystrophic EB to reduce generalized itching [185,194]. Anecdotal success has been reported with ondansetron in EB; however, the same had
been reported for pruritus from cholestatic jaundice, although controlled trials did not confirm efficacy [195].
Similar suggestions were made related to the pruritus
of uremia [196,197], leading to recommendations that
ondansetron should be considered, although clinical
trials are needed in EB.
Other medications that have shown sporadic clinical
success in treating itch in EB include: cyproheptadine;
selective serotonin re-uptake inhibitors (SSRIs; fluoxetine, paroxetine, sertraline, fluvoxamine) [193]; tricyclic
antidepressants (doxepin, amitriptyline, nortriptyline) [192];
opioid antagonists (naloxone, naltrexone); kappa receptor
agonists (butorphanol, dextromethorphan, nalbuphine);
other 5-HT3 receptor antagonists (granisetron, dolasetron); antipsychotic agents (olanzapine, pimozide) and
cannabinoids. These agents and the NK-1 receptor antagonist aprepitant may prove to be useful in certain subsets
of patients, although evidence to guide therapy is lacking
[198] and practitioners are encouraged to pursue the aforementioned therapies based on patient response to prior
medications, potential interactions within the patients
medication list and medication availability (see Box 10).
It is common practice for medications from different
drug classes to be used concurrently and for agents in
the same class to be rotated due to the observation that
a particular medication may have improved efficacy after
intermittent drug holiday.
Good practice points A combination of environmental,
cognitive-behavioral and pharmacologic therapies is available for use for EB-related pruritus, which can be a severe
symptom of the disease.
Conclusions
These guidelines represent the initial effort to organize pain
management for patients with EB based on existing evidence. While the guidelines were developed using current
evidence and a rigorous evaluation process, there are limitations in the clinical use of the recommendations. The two
Table 5 Implementation barriers

1. Availability of resources (for example, medications and equipment)
Page 18 of 23
Table 6 Areas of research

Psychological and integrative approaches:
1. Test the efficacy of well-established cognitive behavioral
interventions for acute and chronic pain management in EB.
2. Develop EB-specific pain assessment measures for both acute and
chronic pain.
3. Evaluate the efficacy of cognitive behavioral therapy for EB-related
pruritus
4. Evaluate the role for Integrative Medicine techniques for the EB
population.
Acute pain:
1. Improve the balance between analgesia and side effects specific to
EB (for example, itching).
2. Establish optimal treatment of needle-related pain.
3. Define the role for ketamine and other non-opioid agents.
Chronic and recurrent pain:
1. Evaluate topical therapies including opioids, local anesthetics and
NSAIDs.
2. Determine optimal environmental interventions for bath and
dressing changes including bath additives (salt, bleach, oatmeal).
3. Define optimal perianal pain therapies.
4. Clarify the role of bone density screening in preventing bone pain
and fractures.
5. Determine the role of topical NSAIDs in treatment of corneal
abrasion pain.
6. Explore the role for various physical and occupational therapy
interventions for joint, bone and back pain.
Infants:
1. Validate observational pain scales in the setting of bandaged infants.
2. Determine the safety and dosing of adjunct medications, such as
gabapentin and topical agents.
Pruritus:
1. Establish the mechanisms of pruritus in EB and effective treatment
thereof.
2. Refine the management of opioid-exacerbated itch.
End of life:
1. Define how best to integrate palliative care into the overall care of
patients with EB prior to end of life.
2. Define optimal treatments for pain at the end of life.
A focused list to represent the broad categories that would benefit from
studies in patients with EB.
broad areas of concern involve practical limitations of implementation and the level of available evidence. Tables 5
and 6 identify issues for implementation of the guidelines
as well as general recommendations areas for research to
enhance the level of evidence.
2. Legal and social restrictions on the use of various medications and

therapies.
3. Limited and uneven distribution of knowledge and expertise
4. International dissemination of guidelines and EB-related information
to local care providers and families (includes translation and access
to electronic and print media)
Additional file
Additional file 1: EB-specific articles that were excluded from use in
making recommendations, with rationales.

Abbreviations
CBT: cognitive behavioral therapy/techniques; CHEOPS: Childrens Hospital of
Eastern Ontario Pain Scale; CRIES: Crying, requires oxygen, Increased vital
signs, Expression and Sleepless Pain Scale; DDEB: dominant dystrophic
epidermolysis bullosa; DEB: dystrophic epidermolysis bullosa (dominant and
recessive types); EB: epidermolysis bullosa; EBS: epidermolysis bullosa simplex
(basal and suprabasal types); FLACC: Face Legs Arms Cry Consolability Pain
Scale; GERD: gastroesophageal reflux disease; JEB: junctional epidermolysis
bullosa (generalized and localized); NIPS: Neonatal Infant Pain Scale;
NMDA: N-methyl-d-aspartate; NSAIDs: non-steroidal anti-inflammatory drugs;
N-PASS: Neonatal Pain Agitation and Sedation Scale; PCA: patient controlled
analgesia; PIPP: Premature Infant Pain Profile; RDEB: recessive dystrophic
epidermolysis bullosa.
Page 19 of 23
3.
4.
5.
6.
7.
Competing interests
The authors declare that they have no competing interests.
8.
Authors contributions
This work was initiated and led by KRG with active input from all authors. JG,
EH, CL, ALJ, AEM, LGM and DSL participated in the review process and
recommendation/guideline draft, see text for details. DSL led the systematic
evidence analysis and provided methodological support and guidance.
Multi-disciplinary clinician input was obtained as was input from patients
and families early in the process (see Acknowledgments, below). The
consensus meeting (see text) was attended in person or via Skype by
KRG, ALJ, EH, JG, CL, LGM and BK (see Acknowledgements). All authors
read and approved the final manuscript.
9.
10.
11.
Acknowledgments
Guideline development was supported by a small grant from DEBRA USA to
defray the costs of travel, accommodation and preparation related to the
consensus meeting, held on 4, 5 May 2012 in Cincinnati, Ohio, USA. The
following members of the original guidelines development committee
helped with initial content development and recommendations: Beverly Inge
Walti, Kara Malcolm, Teresa Mingrone, and Stacy Shipley.
The following Clinician Reviewers are gratefully acknowledged: Anna L.
Bruckner, MD, Elizabeth Ely, RN, PhD, Kim Hazelbaker, RN, Barbara Hoggart,
MD, Richard F. Howard, BSc, FRCA, Anne Lucky, MD, Geraldine Mancuso-Kelly,
RN, Elena Pope, MD, Susan Rowe, RN, Alexandra Szabova, MD, Jean Whalen, RN.
Warm thanks to the following Family and Patient Reviewers: Patsy
DiGiovanna, Michelle Starkey, Natasha Starkey and *Brett Kopelan
(*participated in consensus meeting).
Special thanks to Andrea Ayers (administrative assistant to KRG), Brett
Kopelin (DEBRA USA), Francis Palisson (DEBRA Chile) and Avril Keenan
(DEBRA Ireland) for their support.
Author details
1
Pain Management Center, Department of Anesthesiology, Cincinnati Childrens
Hospital Medical Center, Cincinnati, Ohio, USA. 2Lucille Packard Childrens
Hospital, Department of Anesthesia (by courtesy, Pediatrics), Stanford University,
Stanford, California, USA. 3Helen and Douglas Hospices, Oxford and John
Radcliffe Hospital, Oxford, USA. 4University of Southampton, Southampton, UK.
5
Great Ormond Street Hospital for Children NHS Trust, London, UK. 6Pain
Management Center and Division of Behavioral Medicine and Clinical
Psychology, Cincinnati Childrens Hospital Medical Center, Cincinnati, Ohio, USA.
7
National Paediatric Epidermolysis Bullosa Centre, Great Ormond Street Hospital
NHS Foundation Trust, London, UK. 8Department of Anesthesiology and Critical
Care, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 9James
M. Anderson Center for Health Systems Excellence, Cincinnati Childrens
Hospital Medical Center, Cincinnati, Ohio, USA.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Received: 19 December 2013 Accepted: 9 September 2014
23.
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doi:10.1186/s12916-014-0178-2
Cite this article as: Goldschneider et al.: Pain care for patients with
epidermolysis bullosa: best care practice guidelines. BMC Medicine
2014 12:178.
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Goldschneider et al.

BMC Medicine 2014, 12:178

Pain care for patients with epidermolysis bullosa:

Even then, evidence-based pain care is limited by a near

Goldschneider et al. BMC Medicine 2014, 12:178

literature, guided by expert consensus and thoughtful

autosomal dominant mutations in keratin 5 or 14 or in

Goldschneider et al. BMC Medicine 2014, 12:178

who have any variant of EB. The interventions included,

The guidelines will be updated every three years after

1,046 records identified through

196 records included in

Figure 1 Flow of information through the evidence evaluation process.

Goldschneider et al. BMC Medicine 2014, 12:178

Table 1 EB-specific articles used in producing recommendations

Population (setting, patients)

Chiu 1999 [68]

Country: Canada Setting: Childrens

Amitryptiline (25 mg at night) was

Country: United States Setting:

Pain management and prevention

Herod 2002 [44]

Country: England (London) Setting:

General pain management

Mellerio 2007 [152]

Country: United States, England,

General pain management

Saroyan 2009 [156]

Country: United States Setting:

Use of IV ketamine given orally Oral

Achieve analgesia during

Country: Netherlands Setting:

Interviews conducted at homes or in hospital

Themes of pain for severe

Watterson 2004 [74]

Country: United States Setting:

Topical morphine gel applied to the most

web page for DEBRA International that is dedicated to

Results and discussion

Systematic review, meta-analysis,

Best study design for domain

Fair study design for domain

Weak study design for domain

General review, expert opinion,

a = good quality study; b = lesser quality study.

children with acute and chronic pain [12]. This approach

Psychological therapies for pain management have been

Goldschneider et al. BMC Medicine 2014, 12:178

Table 3 Summary of recommendations

Gerik 2005 [13] (5a), Palermo 2005 [17] (5a)

For acute pain management, offer the patient distraction,

Green 2005 [14] (5a), Uman 2006 [21]

Consider habit reversal training, and other psychological

Goldschneider 2010 [41] (5a), Goldschneider 2010b [42] (5a)

Transmucosal (including intranasal fentanyl and

Manjushree et al., 2002 [45] (2b); Borland et al., 2007 [46]

Perioperative opioid use must account for preoperative

Hartrick 2008 [56] (1a), Mhuircheartaigh 2009 [55] (1a),

Regional anesthesia is appropriate for pain resulting from

Diwan 2001 [51] (5a), Doi 2006 [53] (5b), Englbrecht

Denyer 2010 [57] (5a)

Consider topical therapies for pain

Systemic pharmacologic therapy should be adapted to